The following description is provided to assist the understanding of the reader. None of the information provided or references cited is admitted to be prior art to the present invention.
Obesity has become a worldwide epidemic, the consequences of which represent a major challenge facing human health in the 21st century. A decrease in the sensitivity of skeletal muscle to insulin is one of the earliest maladies associated with obesity, and its persistence is a prominent risk factor for type II diabetes and cardiovascular disease. The accumulation of lipid in skeletal muscle has long been associated with the development of insulin resistance, a maladaptive response that is currently attributed to the generation and intracellular accumulation of proinflammatory lipid metabolites (e.g., fatty acyl-CoAs, diacylglycerols and/or ceramides) and associated activation of stress-sensitive serine/threonine kinases that antagonize insulin signaling. Skeletal muscle from obese individuals is also characterized by profound reductions in mitochondrial function as evidenced by decreased expression of metabolic genes, reduced respiratory capacity, and mitochondria that are smaller and less abundant, leading to speculation that a decrease in the capacity to oxidize fat due to acquired or inherited mitochondrial insufficiency may be an underlying cause of the lipid accumulation and insulin resistance that develops in various metabolic states.